Thrombus means the blood coagulation condition in the heart and the blood vessels of the living body, and by which the blood vessels are narrowed or occlused, and then, the circulation disorder is led in the tissues being dominated by said blood vessel, and the onset of necrosis or edema occurs in these tissues. As a result, various arterial and thrombotic diseases are caused such as myocardial infarction, intra-atrial thrombus in atrial fibrillation, arterial sclerosis, angina pectoris, stroke, pulmonary infarction, deep venous thrombus (DVT), disseminated intravascular coagulation syndrome (DIC), diabetic complications, restenosis after percutanous transluminal coronary angioplasty (PTCA), etc.
Various factors are considered to participate in the formation of thrombus, for example, the change in the conditions of the blood vessel wall, the change in the blood flow speed, and the change in the components of the plasma. The components of thrombus are, for example, platelets, erythrocytes, leukocytes, fibrin, etc.
In many cases, the fibrinolysis (fibrinolytic system) is secondarily activated in the living body in order to lyse microthrombus being formed in the living body. For instance, plasminogen, inactive precursor, is converted into active plasmin (a protease existing mainly in the plasma) by a plasminogen activator being specific to the active site thereof (PA; tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), etc.), and activated plasmin can interrupt the lysine-bond of polypeptide chain of fibrin, by which thrombus is lysed. On the other hand, the activity of PA is controlled by its specific inhibitor, Type 1 plasminogen activator inhibitor (PAI-1).
Therefore, the activity of the fibrinolysis is determined by the valance between the amount of PA, and the PAI-1, both secreted from the vascular endothelial cells, and the increase or decrease in the PAI-1 production in cells, or the change in the activity of PAI-1 molecule per se immediately affect the fibrinolysis in the blood.
In another word, it may be possible to prevent or treat various thrombotic diseases represented by the above-mentioned diseases by acting directly on the vascular endothelial cells and inhibiting PAI-1 activity or the production thereof, and by increasing PA activity.
Under the above circumstances, there have widely been used enzyme preparations such as tissue plasminogen activator, urokinase, streptokinase, etc. for lysis and prevention of thrombus. These drugs have, however, some deficits, for example, they are rapidly inactivated in the blood and as a result they lose their pharmacological activities in a very short time, or they can be administered only by parenteral route but not by oral route.
On the other hand, EP-A-563798 discloses as an antithrombotic agent 3-[(E)-benzylidene]-4-[(E)-3,4,5-trimethoxybenzylidene]-2,5-pyrrolidinedio ne and (E)-2-[(E)-3,4,5-trimethoxybenzylidene]-3-carboxy-4-phenyl-3-butenoic acid methyl ester, but these compounds also have some deficits such as less bio-availability, less safety as a medicament, and stability thereof, for example, (1) low solubility in water, (2) easily metabolized in the liver, (3) toxicity against in the liver and chromosome, etc.
Besides, Nouveau Journal De Chimie, vol. 1, No. 5, p 413-418 (1977) discloses benzylidenesuccinic acid as a product of reduction of electrolytes, but the pharmacological activities thereof have never been disclosed hitherto.